학술논문
Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
Document Type
Author
Amare, Azmeraw T; Thalamuthu, Anbupalam; Schubert, Klaus Oliver; Fullerton, Janice M; Ahmed, Muktar; Hartmann, Simon; Papiol, Sergi; Heilbronner, Urs; Degenhardt, Franziska; Tekola-Ayele, Fasil; Hou, Liping; Hsu, Yi-Hsiang; Shekhtman, Tatyana; Adli, Mazda; Akula, Nirmala; Akiyama, Kazufumi; Ardau, Raffaella; Arias, Bárbara; Aubry, Jean-Michel; Hasler, Roland; Richard-Lepouriel, Hélène; Perroud, Nader; Backlund, Lena; Bhattacharjee, Abesh Kumar; Bellivier, Frank; Benabarre, Antonio; Bengesser, Susanne; Biernacka, Joanna M; Birner, Armin; Marie-Claire, Cynthia; Cervantes, Pablo; Chen, Hsi-Chung; Chillotti, Caterina; Cichon, Sven; Cruceanu, Cristiana; Czerski, Piotr M; Dalkner, Nina; Del Zompo, Maria; DePaulo, J Raymond; Étain, Bruno; Jamain, Stephane; Falkai, Peter; Forstner, Andreas J; Frisen, Louise; Frye, Mark A; Gard, Sébastien; Garnham, Julie S; Goes, Fernando S; Grigoroiu-Serbanescu, Maria; Fallgatter, Andreas J; Stegmaier, Sophia; Ethofer, Thomas; Biere, Silvia; Petrova, Kristiyana; Schuster, Ceylan; Adorjan, Kristina; Budde, Monika; Heilbronner, Maria; Kalman, Janos L; Kohshour, Mojtaba Oraki; Reich-Erkelenz, Daniela; Schaupp, Sabrina K; Schulte, Eva C; Senner, Fanny; Vogl, Thomas; Anghelescu, Ion-George; Arolt, Volker; Dannlowski, Udo; Dietrich, Detlef; Figge, Christian; Jäger, Markus; Lang, Fabian U; Juckel, Georg; Konrad, Carsten; Reimer, Jens; Schmauß, Max; Schmitt, Andrea; Spitzer, Carsten; von Hagen, Martin; Wiltfang, Jens; Zimmermann, Jörg; Andlauer, Till F M; Fischer, Andre; Bermpohl, Felix; Ritter, Philipp; Matura, Silke; Gryaznova, Anna; Falkenberg, Irina; Yildiz, Cüneyt; Kircher, Tilo; Schmidt, Julia; Koch, Marius; Gade, Kathrin; Trost, Sarah; Haussleiter, Ida S; Lambert, Martin; Rohenkohl, Anja C; Kraft, Vivien; Grof, Paul; Hashimoto, Ryota; Hauser, Joanna; Herms, Stefan; Hoffmann, Per; Jiménez, Esther; Kahn, Jean-Pierre; Kassem, Layla; Kuo, Po-Hsiu; Kato, Tadafumi; Kelsoe, John; Kittel-Schneider, Sarah; Ferensztajn-Rochowiak, Ewa; König, Barbara; Kusumi, Ichiro; Laje, Gonzalo; Landén, Mikael, 1966; Lavebratt, Catharina; Leboyer, Marion; Leckband, Susan G; Tortorella, Alfonso; Manchia, Mirko; Martinsson, Lina; McCarthy, Michael J; McElroy, Susan; Colom, Francesc; Millischer, Vincent; Mitjans, Marina; Mondimore, Francis M; Monteleone, Palmiero; Nievergelt, Caroline M; Nöthen, Markus M; Novák, Tomas; O'Donovan, Claire; Ozaki, Norio; Pfennig, Andrea; Pisanu, Claudia; Potash, James B; Reif, Andreas; Reininghaus, Eva; Rouleau, Guy A; Rybakowski, Janusz K; Schalling, Martin; Schofield, Peter R; Schweizer, Barbara W; Severino, Giovanni; Shilling, Paul D; Shimoda, Katzutaka; Simhandl, Christian; Slaney, Claire M; Squassina, Alessio; Stamm, Thomas; Stopkova, Pavla; Maj, Mario; Turecki, Gustavo; Vieta, Eduard; Veeh, Julia; Witt, Stephanie H; Wright, Adam; Zandi, Peter P; Mitchell, Philip B; Bauer, Michael; Alda, Martin; Rietschel, Marcella; McMahon, Francis J; Schulze, Thomas G; Clark, Scott R; Baune, Bernhard T
Source
Molecular psychiatry. 28:5251-5261
Subject
Language
English
ISSN
1476-5578
Abstract
Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.